Biomedical subjects
M Fraccaro
Publications and source records attributed to M Fraccaro.
A ZFY-negative 46,XX true hermaphrodite is positive for the Y pseudoautosomal boundary.
Two loci on the short arm of the human Y chromosome have recently been described as candidates for the testis determining factor (TDF); namely, ZFY, and a locus distal to ZFY, near the pseudoautosomal boundary. We have previously reported on seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case all presenting with testicular tissue in their gonads in the apparent absence of Y-specific DNA sequences. A reanalysis of these cases shows them all to lack ZFY, but one 46,XX true hermaphrodite carries sequences next to the Y pseudoautosomal boundary. This case provides further evidence for assigning the TDF locus very close to the pseudoautosomal region on Yp.
Clonal structural chromosomal rearrangements in lymphocytes of four patients with Werner's syndrome.
Multiple numerical and structural chromosome abnormalities were found in cultured lymphocytes of four patients with Werner's syndrome. The proportion of metaphases with structural and/or numerical aberrations varied from 30 to 44% and several of them were clonal. These results confirm definitively that Werner's syndrome is a chromosome rearrangement syndrome and that these non-constitutional chromosome changes are not exclusive of cultured fibroblasts but present also in lymphocytes.
Multiple clonal chromosome abnormalities in a superficial basal cell epithelioma.
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A syndrome of primary gonadal failure, short stature, mitral valve prolapse, and mental retardation.
Two brothers referred for hypogonadism presented with short stature, mild mental retardation, and minor anomalies. In addition, both patients had hypogonadism due to primary gonadal failure and mitral valve prolapse, in the absence of other heart defects. A complete hormonal evaluation in one of the patients showed abnormal growth hormone (GH) and gonadotropin responses to different stimuli, findings suggestive of a disorder of hypothalamic-pituitary regulation. Both patients had normal chromosomes (46,XY) as did their mother (46,XX), who had some of the clinical manifestations found in her sons but in a milder form. We propose that this is a new syndrome.
Chromosome abnormalities in dyskeratosis congenita.
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Analysis of two 47,XXX males reveals X-Y interchange and maternal or paternal nondisjunction.
Two cases of 47,XXX males were studied, one of which has been published previously (Bigozzi et al. 1980). Analysis of X-linked restriction fragment length polymorphisms revealed that in this case, one X chromosome was of paternal and two were of maternal origin, whereas in the other case, two X chromosomes were of paternal and one of maternal origin. Southern blot analysis with Y-specific DNA probes demonstrated the presence of Y short arm sequences in both XXX males. In one case, the results obtained pointed to a paracentric inversion on Yp of the patient's father. In situ hybridization indicated that the Y-specific DNA sequences were localized on Xp22.3 in one of the three X chromosomes in both cases. The presence of Y DNA had no effect on random X inactivation. It is concluded that both XXX males originate from aberrant X-Y interchange during paternal meiosis, with coincident nondisjunction of the X chromosome during maternal meiosis in case 1, and during paternal meiosis II in case 2.
Localization of Y chromosome sequences and X chromosomal replication studies in XX males.
By in situ hybridization, Y-specific DNA sequences were localized on Xp22.3-Xpter of one of the two X chromosomes in all of eleven XX males studied. In nine of the cases the presence of the Y-specific DNA did not affect random X inactivation in fibroblasts. Fibroblasts of the other two cases showed a preferential inactivation of the Y DNA-carrying X chromosome. In only one of these two exceptions blood lymphocytes could also be studied, and here, random inactivation of the Y DNA-carrying X chromosome occurred. Furthermore, the gene dosage of steroid sulfatase (STS) was examined by Southern blot analysis. In ten of the cases including the one showing random X-inactivation in lymphocytes but not in fibroblasts, a double dosage of the STS gene is present. The remaining case with non-random inactivation shows a single STS gene dosage. This case was reported previously to have STS enzyme activity in the male range. It is assumed that, as a consequence DNA sequences may result in the preferential inactivation of the Y DNA-carrying X chromosome.
A clonal t(9;12)(q32;q21) in cultured fibroblasts from a case of Bowen's disease.
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Clonal chromosome abnormalities with preferential involvement of chromosome 3 in patients with porokeratosis of Mibelli.
Clonal chromosome abnormalities were found in cultured fibroblasts from three sibs and one sporadic case with porokeratosis of Mibelli. Chromosome 3 especially involved region p12-14. This region includes the most common fragile site in humans, and the proximal region of chromosome 3 short arm is involved in a variety of neoplastic conditions. We conclude that porokeratosis of Mibelli, an autosomal dominant disorder, is associated with chromosomal instability. Porokeratosis of Mibelli is known to also be associated with increased susceptibility to malignant disease. The chromosome instability may well predispose to malignancy.
Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome.
Mendelian inherited disorders due to deletions of adjacent genes on a chromosome have been described as "contiguous gene syndromes." Short stature, chondrodysplasia punctata, mental retardation, steroid sulfatase deficiency, and Kallmann syndrome have been found as isolated entities or associated in various combinations in 27 patients with interstitial and terminal deletions involving the distal short arm of the X chromosome. The use of cDNA and genomic probes from the Xp22-pter region allowed us to identify 12 different deletion intervals and to confirm, and further refine, the chromosomal assignment of X-linked recessive chondrodysplasia punctata and Kallmann syndrome genes. A putative pseudoautosomal gene affecting height and an X-linked non-specific mental retardation gene have been tentatively assigned to specific intervals. The deletion panel described is a useful tool for mapping new sequences and orienting chromosome walks in the region.
Analysis of complex Y chromosome aberrations using a single DNA probe (Y-367).
A specific cloned DNA sequence (Y-367) detects at least four loci in the euchromatic long arm and in the short arm of the human Y chromosome. Deletion mapping assigns one locus to the distal euchromatic long arm, another to a region close to the centromere on either Yq or Yp, and two additional loci to the Y short arm. Y-367 may thus be used for the rapid screening of even complex Y chromosome aberrations. This is exemplified in a 45,X male with Y chromosome material on the long arm of chromosome 10 by the detection of an inversion of a portion of Yp and by the confirmation of duplications and deletions in two individuals with duplications of part of the Y chromosome.
Chromosome abnormalities in tuberous sclerosis.
In fibroblasts cultured from biopsies of the skin lesions of six patients with tuberous sclerosis (TS) there was a variable but consistent degree of karyotypic variation. Premature centromere disjunction (PCD) of all or part of the chromosomes, micronuclei, an increased incidence of breaks, dicentric chromosomes and the presence of polyploid metaphases were found in all cultures. The PCD was of the type encountered in Roberts syndrome and its frequency varied from 8% to 30%. In metaphases with PCD of one and of two chromosomes, the chromosome involved were identified, and chromosome 3 was involved 21 times among 59 chromosomes with PCD. Chromosome 3 tends to be preferentially involved in dicentric formation. In lymphocyte cultures from the same patients there were no metaphases with PCD, but there was a slight increase of breaks and the presence of dicentric chromosomes, also involving chromosome 3. Polyploid metaphases were increased in some of the cases. Karyotypic variation can be considered a cellular phenotypic characteristic of TS in fibroblasts cultured from the skin lesions, and its type indicates disturbances in the mechanics of centromere division and of chromosome distribution at cell division.
Shwachman syndrome and chromosome breakage.
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False-positive and false-negative findings on chorionic villus sampling.
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Absence of Y-specific DNA sequences in human 46,XX true hermaphrodites and in 45,X mixed gonadal dysgenesis.
A search for Y-specific DNA sequences has been performed in a sample of seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case and compared with a sample of 11 XX males. Using six Y-specific DNA probes no hybridization signal was obtained in the hermaphrodite group; in contrast, all XX males gave a positive signal with at least one probe. This difference is statistically highly significant. We conclude that the aetiology of true hermaphroditism is different from that of the XX male syndrome. As all cases of the hermaphrodite group are positive for the serological sex-specific antigen (Sxs) it is concluded that this antigen can be present even in the absence of Y-specific DNA.
The origin and phenotype of XO males.
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Prevalence and distribution of chromosome abnormalities in a sample of first trimester internal abortions.
Cytogenetic analysis was performed directly on villus material from 202 samples obtained at the evacuation of the uterine cavity in cases of retained abortion in the first trimester, identified as such by ultrasound examination. A precise delineation of the karyotype was obtained in 94% of the cases, while the efficiency of karyotype analysis in samples of spontaneous abortion was not higher than 50%. An abnormal chromosome constitution was found in 145 fetuses (76.7%) of which 117, including mosaics, were aneuploid (70%), 16 polyploid (8.5%) and 12 had structural abnormalities (6.3%). The relative proportion of chromosome abnormalities in this material is higher than that found in spontaneous abortion for trisomies and double trisomies, but lower for 45,X and polyploidy. The method was found to be efficient in obtaining fetal karyotypes also in those cases in which the villous material was scarce (1 mg), and thus it seems appropriate for routine cytogenetic studies in the first trimester abortions.